brl-15572 and 5-carboxamidotryptamine

The 5-HT1B/1D receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 receptor agonist, and 5-HT5A/5B receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D receptor antagonists. Also, expression of 5-HT5A and 5-HT5B receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 receptors. This mechanism, however, resembles putative 5-HT5B receptors.

Topics: Animals; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergotamine; Hypotension; Oxadiazoles; Piperazines; Piperidones; Rats; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds

1. In the present study, we investigated how alloxan-induced diabetes affects the ability of 5-hydroxytryptamine (5-HT) to modulate bradycardia induced in vivo by electrical stimulation of the vagus nerve in pithed rats. We also analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats with a single injection of alloxan (150 mg/kg, s.c.). Four weeks later, rats were anaesthetized, pretreated with atenolol and pithed. Electrical stimulation (3, 6 and 9 Hz) of the vagus nerve resulted in frequency dependent decreases in heart rate (HR). 3. In diabetic rats, intravenous bolus administration of high doses of 5-HT (100 and 200 microg/kg) increased the bradycardia induced by vagal electrical stimulation. Similarly, low doses (10 microg/kg) of the 5-HT(1/7) receptor agonist 5-carboxamidotryptamine (5-CT), increased vagally induced bradycardia. However, at high doses (50, 100 and 150 microg/kg), 5-CT reduced the bradycardia. Attenuation of the vagally induced bradycardia evoked by the higher doses of 5-CT was reproduced by L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors. Enhancement of the vagally induced bradycardia elicited by low doses of 5-CT was reproduced by the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT; 50 microg/kg). These stimulatory and inhibitory actions on vagal stimulation-induced bradycardia in diabetic rats were also observed after administration of exogenous acetylcholine. 4. Vagally induced bradycardia in diabetic rats was not affected by administration of the selective 5-HT(2) receptor agonist alpha-methyl-5-HT (150 microg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 microg/kg) or the selective 5-HT(1B) receptor agonist CGS-12066B (50 microg/kg). 5. Enhancement of the electrical stimulation-induced bradycardia in diabetic rats caused by 5-CT (10 microg/kg) or 8-OH-DPAT (50 microg/kg) was abolished by the selective 5-HT(2/7) receptor antagonist mesulergine (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 microg/kg), respectively. Similarly, pretreatment with the non-selective 5-HT(1) receptor antagonist methiothepin (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 microg/kg) on the bradycardia induced by vagal electrical stimulation in diabetic rats. BRL-15572 (2 microg/kg), a selective 5-HT(1D) receptor antagonist, inhibited the action of L-694,247 (50

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acetylcholine; Animals; Biphenyl Compounds; Blood Glucose; Bradycardia; Cholinergic Agents; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Electric Stimulation; Ergolines; Heart; Heart Rate; Injections, Intravenous; Male; Methiothepin; Oxadiazoles; Piperazines; Pyridines; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tryptamines; Vagus Nerve

1. In the present study, we analysed the effect of different doses of 5-hydroxytryptamine (5-HT; intravenous infusions of 0.001-40 microg/kg per min) in the autoperfused hindquarters of the rat subjected to electrical stimulation (frequencies of 0.5-20 Hz) of the lumbar chains, investigating the relationship between the adrenergic and serotonergic systems in this vascular bed. 2. Because we observed that 5-HT inhibited the increases in perfusion pressure induced by electrical stimulation of the lumbar chains, we used different agonists and antagonists to analyse the mechanism of action of 5-HT. 3. The effect of 5-HT was inhibited by methiothepin (a non-specific 5-HT receptor antagonist), but not by ritanserin (a selective 5-HT2 receptor antagonist). The effects of 5-HT were mimicked by 5-carboxamidotryptamine (a 5-HT1 receptor agonist) and L-694 247 (a selective 5-HT1D receptor agonist), but not by 8-hydroxy-2-dipropylaminotetralin (a 5-HT1A receptor agonist), CGS-12066B (a 5-HT1B receptor agonist), alpha-methyl-5-HT (a 5-HT2 receptor agonist), 1-(3-chlorophenyl) piperazine (a 5-HT2C receptor agonist) or 1-phenylbiguanide (a 5-HT3 receptor agonist). The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibited the effect of the agonist L-694 247. 4. Our data suggest that 5-HT inhibits the increases in perfusion pressure induced by the electrical stimulation of the lumbar chains, acting on presynaptic 5-HT1D receptors and decreasing the release of noradrenaline from the sympathetic nerves in the hindquarter vascular bed of the rat.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Biguanides; Biphenyl Compounds; Dose-Response Relationship, Drug; Electric Stimulation; Hindlimb; In Vitro Techniques; Infusions, Intravenous; Male; Methiothepin; Oxadiazoles; Perfusion; Piperazines; Pressure; Quinoxalines; Rats; Rats, Wistar; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT3 Receptor Agonists; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Tryptamines; Vasoconstriction

It has been suggested that the external carotid vasodilatation produced by serotonin (5-hydroxytryptamine; 5-HT) in anaesthetised dogs with intact vagosympathetic trunks is mediated by sympatho-inhibitory '5-HT1D' receptors and musculotropic '5-HT1-like' receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors. In pentobarbital-anaesthetised dogs with intact vagosympathetic trunks, 1-min intracarotid (i.c.) infusions of 5-carboxamidotryptamine (5-CT; 0.01-0.3 microg/min), 5-HT (0.3-30 microg/ min), 5-methoxytryptamine (5-MeO-T; 1-100 microg/min) or sumatriptan (1-100 microg/min) dose-dependently increased the external carotid blood flow without affecting blood pressure or heart rate. The selective 5-HT1D receptor agonist, PNU-142633 (1-1000 microg/min), was essentially inactive. After mesulergine (300 microg/kg, i.v.), an antagonist at cardiovascular 5-HT7 receptors, the above responses to 5-HT, 5-CT and 5-MeO-T were blocked, whilst those to sumatriptan remained unaffected. In contrast, after the 5-HT1B/1D receptor antagonist, GR127935 (10 microg/kg, i.v.), the responses to 5-HT, 5-CT and 5-MeO-T were not affected, but those to sumatriptan were abolished. Furthermore, after the selective 5-HT1B receptor antagonist, SB224289 (300 microg/kg, i.v.), the responses to 5-HT, 5-CT and 5-MeO-T were significantly enhanced, whereas those to sumatriptan were abolished. Interestingly, the responses to all these agonists remained unmodified after the selective 5-HT1D receptor antagonist, BRL15572 (300 microg/kg, i.v.). The above results suggest that the '5-HT1-like' receptors, which mediate canine external carotid vasodilatation, display the pharmacological profile of sympatho-inhibitory 5-HT1B receptors and musculotropic 5-HT7 receptors, and confirm the existence of vasoconstrictor 5-HT1B receptors.

Topics: 5-Methoxytryptamine; Acetylcholine; Animals; Biphenyl Compounds; Blood Flow Velocity; Blood Pressure; Carotid Artery, External; Chromans; Dogs; Dose-Response Relationship, Drug; Female; Heart Rate; Hemodynamics; Male; Neuromuscular Junction; Oxadiazoles; Piperazines; Piperidones; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds; Sumatriptan; Sympathetic Nervous System; Vasodilation